Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)

Ricardo Pardo-Lozano, Magí Farré, Samanta Yubero-Lahoz, Brian O'Mathúna, Marta Torrens, Cristina Mustata, Clara Pérez-Mañá, Klaus Langohr, Elisabet Cuyàs, Marcel lí Carbó, Rafael de la Torre, Ricardo Pardo-Lozano, Magí Farré, Samanta Yubero-Lahoz, Brian O'Mathúna, Marta Torrens, Cristina Mustata, Clara Pérez-Mañá, Klaus Langohr, Elisabet Cuyàs, Marcel lí Carbó, Rafael de la Torre

Abstract

The synthetic psychostimulant MDMA (± 3,4-methylenedioxymethamphetamine, ecstasy) acts as an indirect serotonin, dopamine, and norepinephrine agonist and as a mechanism-based inhibitor of the cytochrome P-450 2D6 (CYP2D6). It has been suggested that women are more sensitive to MDMA effects than men but no clinical experimental studies have satisfactorily evaluated the factors contributing to such observations. There are no studies evaluating the influence of genetic polymorphism on the pharmacokinetics (CYP2D6; catechol-O-methyltransferase, COMT) and pharmacological effects of MDMA (serotonin transporter, 5-HTT; COMT). This clinical study was designed to evaluate the pharmacokinetics and physiological and subjective effects of MDMA considering gender and the genetic polymorphisms of CYP2D6, COMT, and 5-HTT. A total of 27 (12 women) healthy, recreational users of ecstasy were included (all extensive metabolizers for CYP2D6). A single oral weight-adjusted dose of MDMA was administered (1.4 mg/kg, range 75-100 mg) which was similar to recreational doses. None of the women were taking oral contraceptives and the experimental session was performed during the early follicular phase of their menstrual cycle. Principal findings show that subjects reached similar MDMA plasma concentrations, and experienced similar positive effects, irrespective of gender or CYP2D6 (not taking into consideration poor or ultra-rapid metabolizers) or COMT genotypes. However, HMMA plasma concentrations were linked to CYP2D6 genotype (higher with two functional alleles). Female subjects displayed more intense physiological (heart rate, and oral temperature) and negative effects (dizziness, sedation, depression, and psychotic symptoms). Genotypes of COMT val158met or 5-HTTLPR with high functionality (val/val or l/*) determined greater cardiovascular effects, and with low functionality (met/* or s/s) negative subjective effects (dizziness, anxiety, sedation). In conclusion, the contribution of MDMA pharmacokinetics following 1.4 mg/kg MDMA to the gender differences observed in drug effects appears to be negligible or even null. In contrast, 5-HTTLPR and COMT val158met genotypes play a major role.

Trial registration: ClinicalTrials.gov NCT01447472.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Plasma Concentrations of MDMA, HMMA,…
Figure 1. Plasma Concentrations of MDMA, HMMA, MDA, and HMA in both genders (mean ± standard error of the mean, SEM; for MDMA and HMMA: women n = 11 vs. men n = 15; for MDA and HMA: women n = 11 vs. men n = 12).
Influence of CYP2D6 genotype in plasma concentrations of HMMA (mean ± SEM; subjects with 2 FA n = 18 vs. with 1 FA n = 8. *p<0.05, **p<0.01.
Figure 2. Influence of gender and genetics…
Figure 2. Influence of gender and genetics (COMT, 5-HTTLPR) on the temporal course of systolic blood pressure (upper-left panel), heart rate (lower-left panel), and oral temperature (right-end panel) (mean ± SEM); women n = 12 vs. men n = 15; COMT, val/val n = 8 vs. met/* n = 18; 5-HTTLPR, l/* n = 18 vs. s/s n = 9).
*p<0.05, **p<0.01. Graph A corresponds to gender differences in OT, graph B corresponds to differences in OT as a function of 5-HTTLPR polymorphisms (l/l n = 11 vs. s/s n = 9). Subjects l/s (n = 7) are not represented for graph clarity, but data almost fully overlaps with the s/s trace.

References

    1. UNODC, United Nations Office on Drugs and Crime Vienna. World Drug Report 2010. United Nations New York 2010. Avalaible: . Accessed 2012 Feb 14.
    1. Schifano F, Corkery J, Naidoo V, Oyefeso A, Ghodse H (2010) Overview of amphetamine-type stimulant mortality data-UK 1997–2007. Neuropsychobiology 61: 122–130.
    1. Martín-Santos R, Torrens M, Poudevida S, Langohr K, Cuyás E, et al. (2010) 5-HTTLPR polymorphism, mood disorders and MDMA use in a 3-year follow-up study. Addict Biol 15: 15–22.
    1. Rogers G, Elston J, Garside R, Roome C, Taylor R, et al.. (2009) The harmful health effects of recreational ecstasy: a systematic review of observational evidence. Health Tecnology Assessment Vol 13: No 6.
    1. de Sola S, Tarancón T, Peña-Casanova J, Espadaler JM, Langohr K, et al. (2008) Auditory event-related potentials (P3) and cognitive performance in recreational ecstasy polydrug users: evidence from a 12-month longitudinal study. Psychopharmacology (Berl) 200: 425–437.
    1. de Sola Llopis S, Miguelez-Pan M, Peña-Casanova J, Poudevida S, Farré M, et al. (2008) Cognitive performance in recreational ecstasy polydrug users: a two-year follow-up study. J Psychopharmacol 22: 498–510.
    1. Becker JB, Hu M (2008) Sex differences in drug abuse. Front Neuroendocrinol 29: 36–47.
    1. Liechti ME, Gamma A, Vollenweider FX (2001) Gender differences in the subjective effects of MDMA. Psychopharmacology (Berl) 154: 161–168.
    1. Allott K, Redman J (2007) Are there sex differences associated with the effects of ecstasy/3,4-methylenedioxymethamphetamine (MDMA)?. Neurosci Biobehav Rev 31: 327–347.
    1. Kolbrich EA, Goodwin RS, Gorelick DA, Hayes RJ, Stein EA, et al. (2008) Plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine after controlled oral administration to young adults. Ther Drug Monit 30: 320–332.
    1. Cuyàs E, Verdejo-García A, Fagundo AB, Khymenets O, Rodríguez J, et al. (2011) The influence of genetic and environmental factors among MDMA users in cognitive performance. PLoS One 6: e27206.
    1. de la Torre R, Farré M, Mathúna BO, Roset PN, Pizarro N, et al. (2005) MDMA (ecstasy) pharmacokinetics in a CYP2D6 poor metaboliser and in nine CYP2D6 extensive metabolisers. Eur J Clin Pharmacol 61: 551–554.
    1. Camí J, Farré M (2003) Drug addiction. N Engl J Med 349: 975–986.
    1. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, et al. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274: 1527–1531.
    1. Harrison PJ, Tunbridge EM (2008) Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology 33: 3037–3045.
    1. Zhou SF (2009) Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance Part I. Clin Pharmacokinet. 48: 689–723.
    1. Perfetti X, O’Mathúna B, Pizarro N, Cuyàs E, Khymenets O, et al. (2009) Neurotoxic thioether adducts of MDMA identified in human urine after Ecstasy ingestion. Drug Metabol Disp 37: 1448–1455.
    1. Yang J, Jamei M, Heydari A, Yeo KR, de la Torre R, et al. (2006) Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA. J Psychopharmacol 20: 842–849.
    1. de la Torre R, Farré M, Ortuño J, Mas M, Brenneisen R, et al. (2000) Non-linear pharmacokinetics of MDMA (“Ecstasy”) in humans. Br J Clin Pharmacol 49: 104–109.
    1. de la Torre R, Farré M, Roset PN, Pizarro N, Abanades S, et al. (2004) Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit 26: 137–144.
    1. Farré M, de la Torre R, Mathúna BO, Roset PN, Peiró AM, et al. (2004) Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics. Psychopharmacology (Berl) 173: 364–375.
    1. Yubero-Lahoz S, Pardo R, Farré M, O’Mahony B, Torrens M, et al. (2011) Sex Differences in 3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy)-Induced Cytochrome P450 2D6 Inhibition in Humans. Clin Pharmacokinet 50: 319–329.
    1. O’Mathúna B, Farré M, Rostami-Hodjegan A, Yang J, Cuyàs E, et al. (2008) The consequences of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) induced CYP2D6 inhibition in humans. J Clin Psychopharmacol 28: 523–529.
    1. Torrens M, Serrano D, Astals M, Pérez-Domínguez G, Martín-Santos R (2004) Diagnosing comorbid psychiatric disorders in substance abusers: validity of the Spanish versions of the Psychiatric Research Interview for Substance and Mental Disorders and the Structured Clinical Interview for DSM-IV. Am J Psychiatry 161: 1231–1237.
    1. Mas M, Farré M, de la Torre R, Roset PN, Ortuño J, et al. (1999) Cardiovascular and neuroendocrine effects and pharmacokinetics of 3,4-methylenedioxymethamphetamine in humans. J Pharmacol Exp Ther 290: 136–145.
    1. Pizarro N, Ortuño J, Farré M, Hernández-López C, Pujadas M, et al. (2002) Determination of MDMA and its metabolites in blood and urine by gas chromatography-mass spectrometry and analysis of enantiomers by capillary electrophoresis. J Anal Toxicol 26: 157–165.
    1. Fagundo AB, Cuyàs E, Verdejo-Garcia A, Khymenets O, Langohr K, et al. (2010) The influence of 5-HTT and COMT genotypes on verbal fluency in ecstasy users. J Psychopharmacol 24: 1381–1393.
    1. Cuyàs E, Olano-Martín E, Khymenets O, Hernández L, Jofre-Monseny L, et al. (2010) Errors and reproducibility of DNA array-based detection of allelic variants in ADME genes: PHARMAchip. Pharmacogenomics 11: 257–266.
    1. Cami J, Farré M, Mas M, Roset PN, Poudevida S, et al. (2000) Human pharmacology of 3,4-methylenedioxymethamphetamine (“ecstasy”): psychomotor performance and subjective effects. J Clin Psychopharmacol 20: 455–466.
    1. Farré M, Abanades S, Roset PN, Peiró AM, Torrens M, et al. (2007) Pharmacological interaction between 3,4-methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological effects and pharmacokinetics. J Pharmacol Exp Ther 323: 954–962.
    1. Gaedigk A, Bradford LD, Marcucci KA, Leeder JS (2002) Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans. Clin Pharmacol Ther 72: 76–89.
    1. McLeod HL, Fang L, Luo X, Scott EP, Evans WE (1994) Ethnic differences in erythrocyte catechol-O-methyltransferase activity in black and white Americans. J Pharmacol Exp Ther 270: 26–29.
    1. Williams RB, Marchuk DA, Gadde KM, Barefoot JC, Grichnik K, et al. (2003) Serotonin-related gene polymorphisms and central nervous system serotonin function. Neuropsychopharmacology 28: 533–541.
    1. Schwartz JB (2007) The Current State of Knowledge on Age, Sex, and Their Interactions on Clinical Pharmacology. Clin Pharmacol Ther 1: 87–96.
    1. Pizarro N, de la Torre R, Joglar J, Okumura N, Perfetti X, et al. (2008) Serotonergic Neurotoxic Thioether Metabolites of 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"): Synthesis, Isolation, and Characterization of Diastereoisomers. Chem Res Toxicol 21: 2272–2279.
    1. Boudíková B, Szumlanski C, Maidak B, Weinshilboum R (1990) Human liver catechol-O-methyltransferase pharmacogenetics. Clin Pharmacol Ther 48: 381–389.
    1. Aitchison KJ, Tsapakis EM, Huezo-Diaz P, Kerwin RW, Forsling ML, et al. (2012) Ecstasy (MDMA)-induced hyponatraemia is associated with genetic variants in CYP2D6 and COMT. J Psychopharmacol 26: 408–418.
    1. Wolff K, Tsapakis EM, Pariante CM, Kerwin RW, Forsling ML, et al. (2012) Pharmacogenetic studies of change in cortisol on ecstasy (MDMA) consumption. J Psychopharmacol 26: 419–428.
    1. Hysek CM, Simmler LD, Ineichen M, Grouzmann E, Hoener MC, et al. (2011) The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA (“ecstasy”) in humans. Clin Pharmacol Ther 90: 246–255.
    1. Liechti ME, Vollenweider FX (2001) Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies. Hum Psychopharmacol 16: 589–598.
    1. Cosgrove KP, Mazure CM, Staley JK (2007) Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry 62: 847–855.
    1. Bethea CL, Lu NZ, Gundlah C, Streicher JM (2002) Diverse actions of ovarian steroids in the serotonin neural system. Front Neuroendocrinol 23: 41–100.
    1. Hagen K, Pettersen E, Stovner LJ, Skorpen F, Holmen J, et al. (2007) High systolic blood pressure is associated with Val/Val genotype in the catechol-o-methyltransferase gene The Nord-Trøndelag Health Study (HUNT). Am J Hypertens 20: 21–26.
    1. Cole JC, Sumnall HR, Smith GW, Rostami-Hodjegan A (2005) Preliminary evidence of the cardiovascular effects of polysubstance misuse in nightclubs. J Psychopharmacol. 19: 67–70.
    1. Parrott AC, Gibbs A, Scholey AB, King R, Owens K, et al. (2011) MDMA and methamphetamine: some paradoxical negative and positive mood changes in an acute dose laboratory study. Psychopharmacology (Berl) 215: 527–536.
    1. Meyer T, Auracher M, Heeg K, Urhausen A, Kindermann W (2007) Effectiveness of low-intensity endurance training. Int J Sports Med. 28: 33–39.
    1. Scharhag-Rosenberger F, Meyer T, Walitzek S, Kindermann W (2009) Time course of changes in endurance capacity: a 1-yr training study. Med Sci Sports Exerc. 41: 1130–1137.
    1. de la Torre R, Farré M, Roset PN, Lopez CH, Mas M, et al. (2000) Pharmacology of MDMA in humans. Ann NY Acad Sci 914: 225–237.
    1. Young EA, Becker JB (2009) Perspective: sex matters: gonadal steroids and the brain. Neuropsychopharmacology 34: 537–538.
    1. Sakai Y, Nishikawa M, Leyton M, Benkelfat C, Young SN, et al. (2006) Cortical trapping of alpha-[(11)C]methyl-l-tryptophan, an index of serotonin synthesis, is lower in females than males. Neuroimage 33: 815–824.
    1. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, et al. (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 100: 6186–6191.
    1. Evans SM (2007) The role of estradiol and progesterone in modulating the subjective effects of stimulants in humans. Exp Clin Psychopharmacol 15: 418–426.
    1. Anker JJ, Carroll ME (2011) Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones. Curr Top Behav Neurosci 8: 73–96.

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